When Clinical Trials Go Too Well

Typically, when a clinical trial is stopped early, it’s bad news. The drug being tested may show unexpected side effects too harmful to continue, the trial may fall short of its patient recruitment goals, or the early results may reveal too marginal a benefit to make the study worth the cost and time. But good news can also bring a clinical trial to a premature halt. One recent example is the ACCOMPLISH trial – a study of combination drug therapies for hypertension that was called short after three years basically for being too successful.

The lengthy acronym ACCOMPLISH stands for Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension. In short, the trial was designed to find the best two-drug combination for people with high blood pressure to reduce the frequency of strokes and heart attacks in such patients. The trial compared a previously-established combination of a diuretic and a drug called an ACE inhibitor to a new combination: ACE inhibitor plus calcium-channel blocker. Both two-drug combos were effective at reducing patients blood pressure, but the new combination (benazepril + amlodipine) won out on reducing cardiovascular events, decreasing the numbers of deaths, hospital visits and other serious incidents by 20 percent.

That result was so promising that the study’s data safety monitoring board – an independent panel of scientists who act as a kind of clinical trial lifeguard team – brought the study to its early end. In essence, the results were so positive for the new treatment combination that it would be unethical to continue treating patients with the older combination. Those positive results, announced in 2008 and published in the New England Journal of Medicine, established a new standard treatment for hypertensive patients.

But hypertension was only one of the targets that the ACCOMPLISH trial was designed to study. High blood pressure doesn’t always appear in isolation, sometimes it is accompanied by other diseases as bad or worse for the patient. Because of the trial’s very large size – over 11,000 patients – it was possible to break out some subgroups that had both hypertension and another disease to test the two drug combinations in their effect on that secondary condition.

In comes George Bakris, a professor of medicine and director of the hypertensive diseases unit at the University of Chicago Medical Center. Bakris, an expert in kidney disease, was one of the researchers who designed the ACCOMPLISH trial – and just as importantly, helped seek out the funding (which eventually came from the drug company Novartis) to make it possible. As such, Bakris was able to incorporate a sub-trial within the larger study to look at the effect of these drug combinations on chronic kidney disease, which affects more than 15 percent of Americans.

Out of the total 11,500 patients, about 1,100 with chronic kidney disease were equally distributed to the two experimental groups. When the larger trial was brought to its surprise ending, so to was the kidney disease trial embedded within. Earlier this year, the results of ACCOMPLISH trial specific to chronic kidney disease were published in The Lancet…and the results were just as promising.

As seen with cardiovascular disease, the number of chronic kidney disease events was reduced in the new combination of benazepril + amlodipine, relative to the old-school treatment of benazepril + diuretic hydrochlorothiazide. The difference was especially promising for patients above the age of 65, an older population that hasn’t been studied in a trial of this size before.

“This was different from all the other trials,” Bakris said. “The people were sicker and older, and it was more reflective of the general US population. The implications of this trial are important in that they really single out a benefit of these combination agents when used initially.”

In fact, for those older patients a particularly clinic-relevant effect may have thwarted by the trial’s abrupt, early end. When chronic kidney disease ultimately leads to the loss of the kidney’s ability to filter blood, patients must regularly undergo the rather unpleasant experience of dialysis. In the ACCOMPLISH trial sample, only 3 subjects older than 65 went on dialysis with the new treatment compared to 10 subjects going on dialysis with the old combination – this just narrowly missed statistical significance. Bakris said he believes that, had the trial lasted one more year, that difference would have been been concrete.

“Stopping the trial early made for more drama for the cardiovascular benefit, but it hurt the kidney data,” Bakris said. “We weren’t able to capture as many events as we could have.”